CN109574860B - Method for preparing vilanterol - Google Patents

Method for preparing vilanterol Download PDF

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CN109574860B
CN109574860B CN201910056495.2A CN201910056495A CN109574860B CN 109574860 B CN109574860 B CN 109574860B CN 201910056495 A CN201910056495 A CN 201910056495A CN 109574860 B CN109574860 B CN 109574860B
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vilanterol
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tert
butanol
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CN109574860A (en
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张启龙
许坤
郑庚修
高令峰
诸葛文云
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Anhui Dexinjia Biopharm Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a method for preparing vilanterol, belonging to the field of drug synthesis. The method comprises the following steps: (1) salicyl alcohol and glyoxylic acid are subjected to addition reaction to generate an intermediate 1; (2) the intermediate 1 is subjected to chiral resolution to obtain a chiral intermediate 2; (3) carrying out acylation reaction on the intermediate 2 and the intermediate 3 to generate an intermediate 4, wherein the intermediate 3 is obtained by carrying out a Delbin reaction on the intermediate 5; (4) and reducing the intermediate 4 to obtain the vilanterol. The method has the advantages of easily obtained raw materials, short synthetic route, production cost reduction, mild reaction conditions and simple operation, and is suitable for industrial production.

Description

Method for preparing vilanterol
Technical Field
The invention belongs to the field of drug synthesis, and relates to a method for preparing vilanterol.
Background
Vilanterol trihydronate is a long-acting beta developed by Kulanin Schker (GSK)2A receptor agonist. The compound preparation of the compound preparation and the fluticasone furoate and the compound preparation of the umeclidinium bromide are approved by FDA respectively in 5 months and 12 months in 2013, and are used for treating obstructive pulmonary disease and asthma. Vilanterol has a molecular weight of 486.4, a molecular formula of C24H33Cl2NO5, CAS: 503068-34-6, the Chinese name: chemical name: (R) -4- [2- [ [6- [ (2, 6-dichlorobenzyl) oxy ] phenyl]-ethoxy radical]Ethyl radical]Amino group]-1-hydroxyethyl group]-2-hydroxyethyl]-2-hydroxymethylphenolThe chemical structural formula is shown as follows:
Figure BDA0001952648080000011
world patent WO2003024439 relates to a method for synthesizing vilanterol, and the specific synthetic route is as follows:
Figure BDA0001952648080000012
the synthesis route is the original research route disclosed by the Kulansu Schke company, and requires more than ten steps of reaction, the synthesis step is longer, and in the later synthesis stage, the product is oily and needs to be purified by a column, so that the method is not beneficial to large-scale production. Wherein, one tert-butyloxycarbonyl group is removed after bis (tert-butyloxycarbonyl) amine is used, so the atom utilization rate is low. Furthermore, TFA removal of Boc is not well controlled and both Bocs are easily removed simultaneously. In the route, a large amount of sodium hydride is also used, the sodium hydride emits a large amount of heat in the reaction process, and the use and storage conditions of the sodium hydride are harsh, so that the potential safety hazard exists in industrial production, and the industrial production is not facilitated. In addition, expensive reagents such as cesium carbonate, bis (t-butoxycarbonyl) amine, CBS, etc. are also used, resulting in an excessively high production cost.
Chinese patents CN101684074 and CN103923058 disclose a method for synthesizing vilanterol, and the specific synthetic route is as follows:
Figure BDA0001952648080000021
the synthetic steps of the route are relatively few, the reaction selectivity of the synthetic compound a and the compound v is high, but the compound v is poor in stability and difficult to synthesize, the storage condition requirement is high, and the chiral purity hardly meets the pharmacopoeia requirement. Finally, debenzylation also needs high-pressure reduction, which has high requirements on equipment, increases cost and limits large-scale industrial production.
World patent WO2003024439 relates to a method for synthesizing vilanterol, and the specific synthetic route is as follows:
Figure BDA0001952648080000022
the reaction conditions of each step of the route are mild, the yield of each step is good, and the operation difficulty is low. However, the synthetic steps of the route are long, a plurality of protecting groups are needed, the reaction steps are increased by protecting and deprotecting functional groups, and a tert-butoxycarbonyl group is removed after bis (tert-butoxycarbonyl) amine is used, so that the atom utilization rate is low, the total synthetic yield is low, the industrial application of the synthetic yield is limited, the construction difficulty of a chiral center is high, and the chiral purity meets the quality requirement with certain difficulty. Therefore, a process with short synthetic route, high yield and good quality needs to be designed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing vilanterol, which has the following technical scheme:
Figure BDA0001952648080000031
the preparation method of the intermediate 1 in the technical scheme is that the intermediate is obtained by adding salicyl alcohol and glyoxylic acid in a solvent medium in the presence of alkali. The reaction solvent is preferably a mixed solvent of water and tetrahydrofuran (volume ratio is 1: 1); the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, and is preferably sodium hydroxide; the molar ratio of the salicyl alcohol to the glyoxylic acid is 1:1 to 1.5, and the preferred molar ratio is 1: 1; the reaction temperature is 50-60 ℃.
The preparation method of the intermediate 2 in the technical scheme is that the intermediate 1 is obtained by manual resolution in a solvent medium. The reaction solvent is one of isopropanol, n-propanol, n-butanol, isobutanol and tert-butanol, wherein the preferred solvent is n-butanol; the resolving agent is one of (S) - (+) -arginine, (S) - (+) -phenylglycine, (S) - (+) -p-hydroxyphenylglycine, (S) - (-) -proline, L-phenylacrylamide, (S) - (-) -phenylglycinol, (S) - (-) -phenylalaninol and S (-) -1-phenylethylamine, wherein (S) - (+) -phenylglycine is preferred.
The preparation method of the intermediate 3 in the technical scheme is that the intermediate is obtained by carrying out a Delbin reaction with urotropin in a solvent medium and carrying out acidification and hydrolysis. The reaction solvent is one of ethyl acetate, tert-butyl acetate, sec-butyl acetate, methyl acetate, isopropanol, ethanol and tert-butanol, wherein the preferable solvent is ethyl acetate; urotropin is 1.1 equivalents; concentrated hydrochloric acid was 6 equivalents (based on intermediate 5) and the reaction temperature was 25 ℃.
The preparation method of the intermediate 4 in the technical scheme is that the intermediate is obtained by acylation reaction in a solvent medium in the presence of a condensing agent. Wherein the condensing agent is one of DCC/DMAP, EDCI/HOBt, DCC/HOBt and EDCI/HOAt, preferably EDCI/HOBt; the base is triethylamine, and the dosage of the base is 1-1.5 molar equivalents of the intermediate 2; the solvent is one of DMF, DMAC, DMSO, acetonitrile, tetrahydrofuran and 1, 4-dioxane, and the preferable solvent is DMF; the reaction temperature was 25 ℃.
The preparation method of the vilanterol in the technical scheme is that an amido bond is reduced by adopting a reducing agent in a solvent medium. The solvent is tetrahydrofuran; the reducing agent is NaBH4-BF3·Et2O、BH3-one of THF, intermediate 4 and NaBH4、 BF3·Et2The molar ratio of O is 1:3: 3.
The invention has the beneficial effects that:
(1) the synthetic route is short. In the existing synthesis technology, acetonylidene reacts with Boc2O is two unavoidable protecting groups, the greatest advantage of the invention is that the synthetic steps are few, the use of the two protecting groups is effectively avoided, the atom utilization rate is increased, and the total yield is improved. (2) The reaction condition is mild. In the prior art route, strong bases such as sodium hydride, potassium trimethylsilanolate and the like are used, and anhydrous operation is required. The invention avoids using strong bases such as sodium hydride, potassium trimethylsilanolate and the like, the reaction temperature in each step does not exceed 100 ℃, the ultralow temperature operation is not needed, and the requirement on anhydrous operation is lower. (3) The production cost is low. The invention takes the salicyl alcohol as the initial raw material, has low price and easily obtained raw material, avoids using cesium carbonate and bisExpensive reagents such as (tert-butyloxycarbonyl) amine, CBS and the like effectively reduce the production cost.
Detailed Description
Example 1:
preparation of intermediate 1:
adding 200mL of water into a 500mL three-necked bottle, adding 13.2g (1.1eq) of sodium hydroxide in batches, cooling to 0-5 ℃, adding 37.2g (1eq) of salicyl alcohol while stirring, then adding 0.68g (1%) of benzyltriethylammonium chloride, fully stirring for 1 hour, slowly dropwise adding 44.4g of 50% glyoxylic acid aqueous solution into a reaction system within 1 hour at the temperature of 0-5 ℃, raising the temperature of the reaction system to 25 ℃, continuing to react for 6 hours, controlling the residual content of the raw materials in the liquid phase to be less than 1%, and finishing the reaction. The temperature of the system is reduced to 0-5 ℃, concentrated hydrochloric acid is used for adjusting the pH value to 2-3, tert-butyl acetate is extracted by 100 multiplied by 2mL, organic phases are combined, 100mL of saturated saline solution and 100mL of water are used for washing in sequence, anhydrous magnesium sulfate is used for drying, filtering and concentrating to obtain white solid, and the crude product is recrystallized by toluene to obtain 50g, the yield is 84%, and the purity is 98%.
Preparation of intermediate 2:
adding 300mL of n-butanol, 30g of intermediate 1 and 22.8g of (S) - (+) -phenylglycine into a 500mL three-necked bottle, heating to 110 ℃, stirring for reaction for 4 hours, cooling to 0-5 ℃, stirring for 3 hours, filtering to obtain a white solid, and drying to obtain 32g of the white solid. Adding the solid into 300mL of methanol, refluxing for 3 hours, cooling to below 0 ℃ overnight, filtering the next day, and drying to obtain 22g of white crystals.
Adding the white crystal into 180mL of ethanol, adding 5.2mL of concentrated hydrochloric acid (12M), stirring for 10 hours at 25 ℃, filtering, concentrating the filtrate under reduced pressure to obtain white crystal, and drying to obtain 10g of product, wherein the total yield is 66.7 percent, and the ee is 98 percent.
Preparation of intermediate 3:
30g of the intermediate 5 is added into 600mL of ethyl acetate, 12g (1.1eq) of urotropin is added, the reaction is carried out for 2h at room temperature, and the liquid phase is controlled to be completely reacted. Filtering and drying to obtain white solid powder, dissolving the white powder in 450mL of ethanol, adding 39mL (6eq) of concentrated hydrochloric acid, stirring at room temperature for 48 hours, concentrating the solvent in vacuum to obtain white solid, dissolving the white solid in 150mL of water, cooling to 0-5 ℃, adjusting the pH to 10 with liquid alkali, extracting with ethyl acetate (100X 2mL), drying the organic phase with anhydrous magnesium sulfate, filtering, and evaporating to dryness to obtain light yellow oily matter 25g with purity of 98% and yield of 90%.
Preparation of intermediate 4:
to a 250mL three-necked flask, intermediate 2(10g), intermediate 3(16g), triethylamine (5.1g), and DMF (50L) were added, and N-hydroxybenzotriazole (6.8g) and EDCI (9.7g) were added with stirring at room temperature, and reacted at 25 ℃ for 3 hours, after which EDCI (0.5g) was added to the system, and the mixture was stirred at room temperature overnight. The next day water (100mL) was added to dilute the reaction solution, extracted with ethyl acetate 50X 2mL, the organic phases combined and washed with 1M hydrochloric acid (60mL), 20% potassium carbonate solution (60mL), water (60mL) in that order, and concentrated to give a residue which was dissolved in toluene (60L), heated to 80 deg.C, cooled with stirring, and stirred at 0-5 deg.C overnight. Suction filtration and washing with toluene (10mL) dried to give 21.5g of a pale yellow solid in 85% yield.
Preparation of vilanterol:
under nitrogen protection, in a 250mL three-necked flask, intermediate 4(10g, 1eq) and NaBH were charged4(2.3g, 3 eq.) 60mL of anhydrous THF was added and BF was slowly dropped at 0 deg.C3·Et2O (8.8g, 3eq), keeping the stability below 5 ℃ in the dropping process, keeping the dropping time for about 20 minutes, keeping the temperature for reaction for 20 minutes after the dropping is finished, returning to the room temperature, heating and refluxing for 4 hours, tracking by TLC or finishing the liquid phase middle control reaction, returning to the room temperature, concentrating the solvent in vacuum, adding dilute hydrochloric acid (2mol/L) to quench the reaction at 0 ℃ until no gas is generated, adjusting the system to be alkaline (pH is approximately equal to 9) by using NaOH solution (w is 15 percent), extracting by using 50mL ethyl acetate for 2 times, and saturating 50L of organic phase by using 50L of saturated NaHCO3Washed, dried and concentrated to obtain 8.5g of light yellow oily matter, the yield is 88 percent and the purity is 98 percent.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims (6)

1. A process for the preparation of vilanterol is as follows:
Figure FDA0003007439060000011
2. the process for producing vilanterol according to claim 1, wherein in step S1, the reaction solvent is a mixed solvent of water and tetrahydrofuran; the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate; the molar ratio of the salicyl alcohol to the glyoxylic acid is 1: 1-1.5; the reaction temperature is 50-60 ℃.
3. The process for preparing vilanterol according to claim 1, wherein in step S2, the resolving agent used is one of (S) - (+) -arginine, (S) - (+) -phenylglycine, (S) - (+) -p-hydroxyphenylglycine, (S) - (-) -proline, L-phenylacrylamide, (S) - (-) -phenylglycinol, (S) - (-) -phenylalaninol, S (-) -1-phenylethylamine; the solvent is one of isopropanol, n-propanol, n-butanol, isobutanol and tert-butanol.
4. The method for preparing vilanterol according to claim 1, wherein in step S3, the condensing agent is one of DCC/DMAP, EDCI/HOBt, DCC/HOBt, EDCI/hoaat; the used alkali is triethylamine, and the dosage is 1-1.5 molar equivalent of the intermediate 2; the reaction solvent is one of DMF, DMAC, DMSO, acetonitrile, tetrahydrofuran and 1, 4-dioxane.
5. The process for producing vilanterol according to claim 1, wherein in step S4, the solvent used is tetrahydrofuran; the reducing agent is NaBH4-BF3·Et2O、BH3-one of THF; intermediate 4 with NaBH4、BF3·Et2The molar ratio of O is 1:3:3, the intermediate 4 and BH3The molar ratio of THF is 1: 2.
6. The process for preparing vilanterol according to claim 1, wherein in step S5, the reaction solvent is one of ethyl acetate, tert-butyl acetate, sec-butyl acetate, methyl acetate, isopropanol, ethanol, tert-butanol; based on the intermediate 5, the urotropin accounts for 1-1.5 equivalent, and the concentrated hydrochloric acid accounts for 6 equivalents.
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CN104744271A (en) * 2013-12-26 2015-07-01 成都伊诺达博医药科技有限公司 New process for synthesizing vilanterol
US20150239862A1 (en) * 2012-09-13 2015-08-27 Perrigo Api Ltd. Process for the preparation of vilanterol and intermediates thereof
WO2017001907A1 (en) * 2015-06-29 2017-01-05 Teva Pharmaceuticals International Gmbh Biocatalytic processes for the preparation of vilanterol

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CN101684074A (en) * 2008-09-28 2010-03-31 中山大学 Unsymmetrical hydrogen transfer synthetic method of (R)-salmeterol
US20150239862A1 (en) * 2012-09-13 2015-08-27 Perrigo Api Ltd. Process for the preparation of vilanterol and intermediates thereof
CN104744271A (en) * 2013-12-26 2015-07-01 成都伊诺达博医药科技有限公司 New process for synthesizing vilanterol
WO2017001907A1 (en) * 2015-06-29 2017-01-05 Teva Pharmaceuticals International Gmbh Biocatalytic processes for the preparation of vilanterol

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